[7] In 2009, Henderson was chosen as the Liberal Party candidate for the federal seat of Corangamite,[8] but was defeated by ALP incumbent Darren Cheeseman in the 2010 election.

On 26 May 2019, Victorian Senator Mitch Fifield chose to accept a position as the Permanent Australian Representative in the United Nations, leaving the possibility that the Liberal Party would choose Henderson to fill the casual vacancy caused by Fifield's eventual resignation to accept the role.

[11][12] After the Coalition's defeat at the 2022 federal election, Henderson was appointed to new opposition leader Peter Dutton's shadow cabinet.

[13] However, following losing her seat at the 2019 Federal Election and being appointed to fill a casual senate vacancy, she urged Victorian Premier Daniel Andrews to lift the moratorium on conventional on-shore gas mining, saying to the Senate "Victoria is at a tipping point, facing blackouts over summer, with now the highest electricity prices in the nation.

We need more dispatchable power – taking gas out of the Otway Basin onshore, as the state permits offshore, is desperately required.

We are very very concerned ... it's unnecessary and it's all about politics and not about substance", while previously stating that those requiring medical treatment could already access assistance on Manus Island and Nauru.

[22] In a statement, released in June 2015, she stated that marriage equality "is consistent with fundamental Liberal values which embrace freedom of the individual and stable, long-term relationships".

[23] Henderson is pro-choice on the issue of abortion, which has drawn ire from more conservative elements within the Victorian Liberal Party.

[24] Nonetheless, on the floor of Parliament, on the question on whether the federal government should ensure that all Australians have access to abortion services, Henderson has almost always voted along party lines.

In October 2017, she tweeted an article written by former Prime Minister Paul Keating arguing against such legislation, adding that Victoria's euthanasia bill would "embed a culture of dying" in the state.

[28] In early November 2022, Henderson wrote to ABC (her former employer) managing director David Anderson "requesting disclosure of the remuneration packages for employees, contractors, subcontractors, or other workers earning an annual salary of at least $230,000" among other information sought.